Project 1 PROJECT SUMMARY Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis caused by mutations in the DHCR7 gene which encodes for 7-dehydrocholesterol-delta7-reductase, an enzyme necessary for the production of cholesterol in the body. Affected individuals exhibit multiple malformations and intellectual disability. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of cholesterol precursors. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. The long-term goal of this study is to learn as much as possible about SLOS by following a cohort of patients with SLOS over time, and to build a comprehensive SLOS patient registry and identify biomarkers that can be used for diagnostic testing, screening and outcome measures in future therapeutic trials. Although most patients are treated with enteral cholesterol, there is no evidence that cholesterol supplementation is beneficial. The first aim of the study is thus to determine if cholesterol supplementation predicts changes in developmental and behavioral outcomes over time. The second aim of the study is to take advantage of this cohort of well-characterized patients to follow them over time and better define the clinical and biochemical phenotypes of the disease (biomarkers) using a natural history study design. To accomplish these aims, we plan to measure cholesterol and other sterol levels, perform clinical observations, measure changes in whole body cholesterol pool size as a result of enteral cholesterol supplementation, and conduct imaging studies (brain MRI) to learn more about disease mechanisms and progression, variations in the clinical features among individuals with SLOS, and evaluate the effect of cholesterol supplementation in this condition.